EP0011963B1 - Heterocyclische Carboxamidin-Verbindungen, ihre Herstellung und diese enthaltende pharmazeutische Zusammensetzungen - Google Patents

Heterocyclische Carboxamidin-Verbindungen, ihre Herstellung und diese enthaltende pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0011963B1
EP0011963B1 EP79302564A EP79302564A EP0011963B1 EP 0011963 B1 EP0011963 B1 EP 0011963B1 EP 79302564 A EP79302564 A EP 79302564A EP 79302564 A EP79302564 A EP 79302564A EP 0011963 B1 EP0011963 B1 EP 0011963B1
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Prior art keywords
alkyl
formula
phenyl
hydrogen
ylidene
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Expired
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French (fr)
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EP0011963A1 (de
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Barrie Christian Charles Cantello
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings

Definitions

  • This invention relates to a class of novel heterocyclic compounds which are useful in the treatment of diabetes.
  • the invention also relates to a process for their preparation and to pharmaceutical compositions containing them.
  • the compound of formula (I) has been reported to be useful in the treatment of diabetes in Belgian Patent No. 852,565 and in Diabetes, 27, 856 and 868 (1978).
  • the present invention provides a compound of formula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof:
  • Suitable quaternary salts of compound (II) include C 1-6 alkyl halides, di-C 1-6 alkyl sulphates and benzyl halides.
  • Preferred quaternary salts are the C 1-6 alkyl halides; in particular the methylhalide, such as the methvliodide salt.
  • Suitable acid addition salts of compound (II) include inorganic salts such as the sulphate, nitrate phosphate and borate, hydrohalides such as the hydrochloride, hydrobromide and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate and p-toluenesulphonate.
  • Preferred salts are hydrohalide salts.
  • the group X in compounds of formula (II) preferably represents sulphur and n is preferably zero.
  • Examples of suitable C 1-6 alkyl groups which R' to R 5 and R 7 may represent include methyl, ethyl, n- and iso-propyl, and n-, sec-, iso-, and tert-butyl.
  • cycloalkyl groups which R' and R 2 may represent include cyclopentyl and cyclohexyl.
  • Suitable substituents for the phenyl and benzyl groups for R 5 and the phenyl group for R 6 include ortho-, meta- and para- methyl, methoxy, chloro and bromo.
  • n is zero.
  • R', R 2 and R 7 represent hydrogen, methyl, ethyl, or n-propyl.
  • R' and R 2 are both hydrogen.
  • n is 1, then preferably R 7 is hydrogen.
  • R 3 is methyl, ethyl, n-propyl, or phenyl.
  • R 3 represents hydrogen or C 1-6 alkyl, especially methyl or ethyl.
  • R 4 is hydrogen, methyl, ethyl or n-propyl
  • R 5 represents methyl, ethyl, n-propyl, phenyl or benzyl.
  • suitable such rings include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine and 4-(C 1-6 alkyl)piperazine, for example 4-methylpiperazine rings.
  • R 6 is phenyl
  • Compounds of formula (11) include the following:
  • Compounds of formula (II) may be prepared by reacting a compound of formula (IV) or a salt thereof: wherein R 1 , R 2 , R 3 , R 6 , R 7 , n and X are as defined with respect to formula (II) above and R 15 represents C 1-6 alkyl; with an amine of formula R 4 R 5 NH, wherein R 4 and R 5 are as defined with reference to formula (II) above and thereafter where desired converting a free base of formula (II) so obtained into a pharmaceutically acceptable salt or converting a salt of a compound of formula (II) so obtained into the free base.
  • the reaction is conveniently carried out in polar organic solvent, the choice of which is not critical to the success of the reaction provided that it forms a homogeneous solution of the reagent and is substantially inert to the reagent and product. It has been found that lower alkanols such as iso- propanol are particularly convenient.
  • the reaction is generally carried out at a moderate temperature i.e. greater than room temperature, the reflux temperature of the solvent being selected for convenience.
  • the period for which the reaction is allowed to proceed depends upon the particular starting materials employed.
  • the course of the reaction may be followed by conventional methods such as thin layer chromatography and terminated when an optimum quantity of product is present in the reaction mixture.
  • Example of lower alkyl groups which R 15 may represent include methyl, ethyl, n-propyl or n-butyl but preferably R' 5 represents methyl.
  • intermediates (IV) are prepared by alkylation of a thiourea (VI) using an alkylating agent R 15 .
  • R 15 is as defined with reference to formula (IV) and Z is a leaving group such as chloride, bromide or iodide.
  • the reaction is carried out in a polar organic solvent, the choice of which is not critical provided that the solvent is substantially inert to the reagents and product. Suitable solvents include lower alkanones and alcohols. The reaction is suitably carried out at the boiling point of the solvent.
  • the thiourea (VI) is in turn prepared by reacting an iso-thiocyanate R 6 . NCS with a corresponding imino compound (V), where R', R 2 , R 3 , R 6 , R 7 n and X are as defined with reference to formula (II).
  • This reaction is carried out in a solvent such as toluene, benzene, dioxane, tetrahydrofuran, methanol or ethanol.
  • the reaction is carried out at non-extreme temperatures, i.e up to and including the reflux temperature of the solvent.
  • Compounds of formula (II) may also be prepared by reacting a compound of formula (VII). wherein R 4 , R 5 and R 6 are as defined with respect to formula (II) above; with an imino compound (V), where R', R 2 , R 3 , R 7 , n and x are as defined with respect to formula (II) above and thereafter where desired converting a free base of formula (II) so obtained into a pharmaceutically acceptable salt or converting a salt of a compound of formula (II) so obtained into the free base.
  • the reaction is conveniently carried out in a non-hydroxylic solvent system such as an ether, chlorinated hydrocarbon or a mixture thereof. Suitable solvent systems include mixtures of diethyl ether and chloroform.
  • a non-hydroxylic solvent system such as an ether, chlorinated hydrocarbon or a mixture thereof.
  • Suitable solvent systems include mixtures of diethyl ether and chloroform.
  • the reaction is suitably carried out at ambient temperature. The period for which the reaction is allowed to proceed may be determined by methods as described hereinbefore; however, we have found it convenient to leave the reaction mixture to stand overnight.
  • the reaction is carried out in ethereal solvent such as diethyl ether of tetrahydrofuran.
  • the reaction is suitably carried out at ambient temperature.
  • the period for which the reaction is allowed to proceed may be determined by methods as described hereinbefore; however, we have found a two hour reaction time to be sufficient.
  • the quaternary ammonium salts of compounds of formula (II) may be prepared by reaction of the compounds of formula (II) with the corresponding quaternisation agent for example (C 1-6 ) alkyl, or benzyl halides such as methyl iodide, ethyl bromide, propyl bromide, or benzyl chloride, or sulphuric esters e.g. di(C,_ alkyl)sulphates such as dimethyl sulphate or diethyl sulphate.
  • the corresponding quaternisation agent for example (C 1-6 ) alkyl, or benzyl halides such as methyl iodide, ethyl bromide, propyl bromide, or benzyl chloride, or sulphuric esters e.g. di(C,_ alkyl)sulphates such as dimethyl sulphate or diethyl sulphate.
  • the quatemisation may be carried out in the presence or absence of a solvent, depending upon whether the quaternisation agent is or is not itself capable of acting as a solvent, at ambient temperature or under cooling, and under atmospheric pressure or under pressure in a sealed container.
  • Organic solvents which are inert as regards the reaction and which are suitable for this purpose are ethers such as diethyl ether or tetrahydrofuran, hydrocarbons such as benzene or heptane, ketones such as acetone or butanone, and C '-6 alkanols such as ethanol, propanol or butanol.
  • the anionic function of the quaternary salt can readily be exchanged by a traditional ion exchange technique.
  • compositions in a variety of dosage forms.
  • This invention therefore also includes a pharmaceutical composition which comprises a compound of formula (II) together with a pharmaceutically acceptable carrier or excipient.
  • compositions may be formulated for administration by any route, although an oral administration is preferred.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxy-methyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxy benzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxy-methyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1 % to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • the dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient but will normally be in the range 0.5 to 150 mg/kg/day.
  • Mpt 130-2° was prepared by an analogous procedure to that described in Example (1b).
  • N,N-diethyl-N'-(3-methylthiazolidin-2-ylidene)-N"-phenylguanidine as an oil, purified by column chromatography on silica using 5% of (33% dimethylamine in IMS) in CH 2 Cl 2 as eluent.
  • N-(3-methyloxazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine-carboxamidine as an oil, purified by chromatography using 1% of (33% dimethylamine in 1 MS) in CH 2 Cl 2 as eluent.
  • mice were fasted for 24 hours before the experiment and then randomised so that each treatment group contained 8 mice.
  • the compounds were dosed orally in 1% aqueous carboxy- methyl cellulose (10 ml/kg body weight), and 30 minutes later glucose (1 g/kg) was administered by the sub-cutaneous route.
  • Blood samples for glucose analysis were taken from the tail 60 minutes after glucose administration; the results are shown in the table below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (29)

1. Ein Verfahren zur Herstellung einer Verbindung der Formel (II) oder eines pharmakologisch verträglichen quartären Ammonium- oder Säureadditionssalzes derselben:
Figure imgb0048
 in der X Sauerstoff oder Schwefel darstellt;
n 0 oder 1 darstellt;
R7 Wasserstoff oder einen C1-6-Alkylrest darstellt;
R' und R2 gleich oder verschieden sind und Wasserstoff, einen C1-6-Alkyl-, Phenyl-, Benzyl- oder C3-6-Cykloalkylrest darstellt;
R3 Wasserstoff, einen C1-6-Alkyl-, Phenyl- oder Benzylrest darstellt;
R4 Wasserstoff oder einen C1-6-Alkylrest darstellt;
R5 einen C1-6-Alkylrest, einen Phenylrest, der gegebenenfalls mit bis zu 3 Gruppen, ausgewählt aus Halogen, C1-6-Alkoxy-resten, substituiert ist, oder einen Benzylrest, der gegebenenfalls mit bis zu 3 Gruppen, ausgewählt aus Halogen, C1-6-Alkyl- und C1-6-Alkoxyresten substituiert ist, darstellt; oder R4 und R5 zusammen die Restglieder eines 5- oder 6-gliedrigen Rings bilden, der gegebenenfalls ein Sauerstoff-, Schwefel- oder zusätzliches Stickstoffatom enthält und gegebenenfalls mit C1-6-Alkyl-, Carboxy- oder C1-6-Alkoxycarbonylresten substituiert ist; und
R6 einen Phenylrest darstellt, der gegebenenfalls mit bis zu 3 Gruppen, ausgewählt aus Halogen, C1-6-Alkyl-, C1-6-Alkoxy-, C1-6-Alkanoyl-, C1-6-Alkanoyloxy-, Nitro-, Hydroxy-, Amino-, Carboxy- und C1-6-Alkoxycarbonylgruppen, substituiert ist, mit der Maßgabe, daß die Verbindungen, in denen gleichzeitig
R3 die Methylgruppe;
R4 die Methyl- oder Äthylgruppe, und
R5 ein niederer Alkyl- oder Benzylrest ist oder
Figure imgb0049
zusammen genommen
Figure imgb0050
darstellt, in denen W ein Sauerstoff- oder Schwefelatom oder ein N-nieder- Alkylrest ist, ausgenommen sind, die Maßnahmen umfassend, daß entweder:
a) eine Verbindung der Formel (IV) oder ein Salz derselben:
Figure imgb0051
in der R1, R2, R3, R6, R7, n und X wie in Formel (II) oben definiert sind und R'5 einen C1-6-Alkylrest darstellt, mit einem Amin der Formel R4R5NH umgesetzt wird, in der R4 und R5 wie in Formel (II) oben definiert sind; oder
b) eine Verbindung der Formel (VII):
Figure imgb0052
in der R4, R5, und R6 wie in Formel (II) oben definiert sind, mit einer Iminoverbindung (V) umgesetzt wird:
Figure imgb0053
in der R', R2, R3, R7, n und X wie in Formel (II) oben definiert sind, und anschließend gewünschtenfalls eine so erhaltene freie Base der Formel (II) in ein pharmakologisch verträgliches Salz umgewandelt wird oder ein so erhaltenes Salz einer Verbindung der Formel (II) in die freie Base umgewandelt wird.
2. Ein Verfahren gemäß Anspruch 1, wobei n 0 ist.
3. Ein Verfahren gemäß Anspruch 1, wobei R7 ein Wasserstoffatom und n 1 ist.
4. Ein Verfahren gemäß einem der Ansprüche 1 bis 3, wobei R' und R2 Wasserstoffatome darstellen.
5. Ein Verfahren gemäß einem der Ansprüche 1 bis 3, wobei R3 ein Wasserstoffatom oder einen C1-6-Alkylrest darstellt.
6. Ein Verfahren gemäß Anspruch 6, wobei R3 eine Methyl- oder Äthylgruppe darstellt.
7. Ein Verfahren gemäß einem der Ansprüche 1 bis 6, wobei R4 und R5zusammen die Restglieder eines 5- oder 6-gliedrigen Rings darstellen, der gegebenenfalls ein Sauerstoff-, Schwefel- oder ein zusätzliches Stickstoffatom enthält und gegebenenfalls mit einem C1-6-Alkyl-, Carboxy- oder C1-6- Alkoxycarbonylrest substituiert ist.
8. Ein Verfahren gemäß Anspruch 7, wobei R4 und R5 einen Pyrrolidin-, Piperidin-, Morpholin-, Thiomorpholin-, Piperazin- oder 4(C1-6-Alkyl)-Piperazinring vervollständigen.
9. Ein Verfahren zur Herstellung einer Verbindung gemäß Anspruch 1 der Formel (III) oder eines pharmakoligisch verträglichen quartären Ammonium- oder Säureadditionssalzes derselben:
Figure imgb0054
in der R8 und R9 Wasserstoff oder C1-6-Alkylreste darstellen;
R10 ein Wasserstoffatom oder einen C1-6-Alkylrest darstellt;
R" und R'2 zusammen die Restglieder eines 5- oder 6-gliedrigen Rings darstellen, der gegebenenfalls ein Sauerstoff- oder ein zusätzliches Stickstoffatom enthält und gegebenenfalls mit einem C1-6- Alkylrest substituiert ist; und
R14 ein Wasserstoffatom, einen C1-6-Alkylrest oder ein Halogenatom darstellt.
10. Ein Verfahren gemäß Anspruch 1 oder 2, wobei R4 und R5 zusammen ―(CH2)4―, ―CH2O(CH2)2 ―,―(CH2)2O(CH2)2―, ―(CH2)NRx(CH2)2― oder ―(CH2)2NRx(CH2)2― darstellen, in denen Rx ein Wasserstoffatom oder ein C1-6-Alkylrest ist. '
EP79302564A 1978-11-29 1979-11-14 Heterocyclische Carboxamidin-Verbindungen, ihre Herstellung und diese enthaltende pharmazeutische Zusammensetzungen Expired EP0011963B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT79302564T ATE1339T1 (de) 1978-11-29 1979-11-14 Heterocyclische carboxamidin-verbindungen, ihre herstellung und diese enthaltende pharmazeutische zusammensetzungen.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB4653178 1978-11-29
GB7846531 1978-11-29
GB7915737 1979-05-05
GB7915737 1979-05-15

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EP0011963A1 EP0011963A1 (de) 1980-06-11
EP0011963B1 true EP0011963B1 (de) 1982-07-14

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US (2) US4250173A (de)
EP (1) EP0011963B1 (de)
AU (1) AU5263779A (de)
DE (1) DE2963350D1 (de)
DK (1) DK485979A (de)
ES (2) ES8101589A1 (de)
IL (1) IL58681A0 (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4414211A (en) * 1978-09-18 1983-11-08 Mcneilab, Inc. Heterocyclic derivatives of guanidine
ATE2075T1 (de) * 1979-04-20 1983-01-15 Beecham Group Plc Oxazolin- und thiazolin-derivate, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische zusammensetzungen.
US4342764A (en) * 1979-05-29 1982-08-03 Ciba-Geigy Corporation Guanidine compounds, pharmaceutical compositions and use
EP0028883A3 (de) * 1979-11-10 1981-06-03 Beecham Group Plc Benzimidazolin-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen
US4421748A (en) * 1982-07-13 1983-12-20 Trager Seymour F Artificial tear aid
US4704389A (en) * 1986-03-05 1987-11-03 Merrell Dow Pharmaceuticals Inc. Aromatic omega-alkyl-imino-tetrahydro-6H-1,3-thiazin-6-one derivatives
GB8903592D0 (en) * 1989-02-16 1989-04-05 Boots Co Plc Therapeutic agents
IT1277486B1 (it) * 1994-12-14 1997-11-10 Japan Tobacco Inc Derivati di tiazina o di tiazepina
JP2001261652A (ja) 2000-03-21 2001-09-26 Suntory Ltd 二置換イミノヘテロサイクリック化合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1247318B (de) * 1960-10-13 1967-08-17 Albert Ag Chem Werke Verfahren zur Herstellung von N-[5-Chlormethyloxazolinyl-(2)]-thioharnstoffderivaten
US3758491A (en) * 1972-01-07 1973-09-11 Parke Davis & Co Novel anti infective agents and means of producing the same
DE2205744A1 (de) * 1972-02-08 1973-08-09 Thomae Gmbh Dr K Neue durch einen guanidinylidenrest substituierte heterocyclen und verfahren zu ihrer herstellung
CS225804B2 (cs) 1976-03-19 1984-02-13 Mcneilab Inc Způsob výroby heterocyklických derivátů guanidinu

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EP0011963A1 (de) 1980-06-11
DK485979A (da) 1980-05-30
AU5263779A (en) 1980-05-29
ES493859A0 (es) 1981-11-16
ES486422A0 (es) 1980-12-16
US4250173A (en) 1981-02-10
IL58681A0 (en) 1980-02-29
US4282356A (en) 1981-08-04
ES8200669A1 (es) 1981-11-16
DE2963350D1 (en) 1982-09-02
ES8101589A1 (es) 1980-12-16

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